Dinuclear Cu(I) mesocate complexes for ROS-mediated DNA cleavage

Copper complexes are promising candidates for anticancer applications due to their redox properties, which enable the generation of reactive oxygen species (ROS) capable of inducing DNA damage, along with their cytotoxic properties. Most of the reported copper-based anticancer agents rely on Cu(II) precursors that require in situ reduction to Cu(I) to exert the therapeutic action. Herein, we report the synthesis and full characterization of two dinuclear copper(I) complexes, [Cu₂L₂Cl₂]·3CH₃OH (C1) and [Cu₂L₂Br₂] (C2) (L = 1,2-bis((E)-2-(diphenylphosphane)benzylidene)hydrazine), displaying a mesocate architecture. C1 and C2·2CH₂Cl₂ constitute the first examples of Cu(I) mesocates showing a [P₂NX] kernel, X = Cl, Br. The effect of the halide ligand of the mesocates on the artificial nuclease activity was evaluated, revealing enhanced activity for the bromide mesocate C2 compared to the chloride analogue C1. Mechanistic studies support an oxidative DNA cleavage pathway involving the generation of hydrogen peroxide. DNA-binding interactions were investigated by cyclic voltammetry, circular dichroism, UV-Vis spectroscopy and competitive fluorescence assays, indicating a predominant groove-binding mode.